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Cited by 88Single-cell and spatial transcriptomicsGenomics and Chromatin DynamicsGene Regulatory Network Analysis

Identification of genomic enhancers through spatial integration of single‐cell transcriptomics and epigenomics

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Bravo González‐Blas, Carmen, Quan, Xiao‐Jiang, Duran‐Romaña, Ramon, Taskiran, Ibrahim Ihsan, Koldere, Duygu, Davie, Kristofer, Christiaens, Valerie, Makhzami, Samira +6 more·2020·Molecular Systems Biology
DOI 10.15252/msb.20209438PMC PMC7237818

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Abstract

Single‐cell technologies allow measuring chromatin accessibility and gene expression in each cell, but jointly utilizing both layers to map bona fide gene regulatory networks and enhancers remains challenging. Here, we generate independent single‐cell RNA‐seq and single‐cell ATAC‐seq atlases of the Drosophila eye‐antennal disc and spatially integrate the data into a virtual latent space that mimics the organization of the 2D tissue using ScoMAP (Single‐Cell Omics Mapping into spatial Axes using Pseudotime ordering). To validate spatially predicted enhancers, we use a large collection of enhancer–reporter lines and identify ~ 85% of enhancers in which chromatin accessibility and enhancer activity are coupled. Next, we infer enhancer‐to‐gene relationships in the virtual space, finding that genes are mostly regulated by multiple, often redundant, enhancers. Exploiting cell type‐specific enhancers, we deconvolute cell type‐specific effects of bulk‐derived chromatin accessibility QTLs. Finally, we discover that Prospero drives neuronal differentiation through the binding of a GGG motif. In summary, we provide a comprehensive spatial characterization of gene regulation in a 2D tissue.

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  • In Drosophila, approximately 70-90% of accessible regions are active enhancers when their accessibility is cell type specific.

    “In Drosophila, different studies have reported that ~70-90% of accessible regions are active enhancers, when their accessibility is cell type specific10–12”

    From Enhancer grammar of liver cell types and hepatocyte zonation states (2022) · cites this paper as [11]

    The Results (page unavailable) report that accessibility and activity correlate in 77% of tested enhancer–reporter regions, and that specifically accessible enhancers tend to show matching activity. The Introduction (page unavailable) also reports that about 74% of 31 predicted cell-type-specific enhancers showed expected activity. These figures concern selected or predicted enhancers, not the proportion of all cell-type-specifically accessible regions that are active enhancers. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 101

  1. Aerts S, Van Loo P, Thijs G, Mayer H, de Martin R, Moreau Y, De Moor B (2005) TOUCAN 2: the all‐inclusive open source workbench for regulatory sequence analysis. Nucleic Acids Res 33: W393– W396 15980497 PMC1160115
  2. Aerts S, Quan X‐J, Claeys A, Naval Sanchez M, Tate P, Yan J, Hassan BA (2010) Robust target gene discovery through transcriptome perturbations and genome‐wide enhancer predictions in Drosophila uncovers a regulatory basis for sensory specification. PLoS Biol 8: e1000435 20668662 PMC2910651
  3. Agawa Y, Sarhan M, Kageyama Y, Akagi K, Takai M, Hashiyama K, Wada T, Handa H, Iwamatsu A, Hirose S et al (2007) Drosophila Blimp‐1 is a transient transcriptional repressor that controls timing of the ecdysone‐induced developmental pathway. Mol Cell Biol 27: 8739– 8747 17923694 PMC2169387
  4. Ahn Y, Zou J, Mitchell PJ (2011) Segment‐specific regulation of the Drosophila AP‐2 gene during leg and antennal development. Dev Biol 355: 336– 348 21575621 PMC3118927
  5. Anderson AM, Weasner BM, Weasner BP, Kumar JP (2012) Dual transcriptional activities of SIX proteins define their roles in normal and ectopic eye development. Development 139: 991– 1000 22318629 PMC3274360
  6. Angerer P, Haghverdi L, Büttner M, Theis FJ, Marr C, Buettner F (2016) Destiny: diffusion maps for large‐scale single‐cell data in R. Bioinformatics 32: 1241– 1243 26668002
  7. Ariss MM, Islam ABMMK, Critcher M, Zappia MP, Frolov MV (2018) Single cell RNA‐sequencing identifies a metabolic aspect of apoptosis in Rbf mutant. Nat Commun 9: 1– 13 30479347 PMC6258665
  8. Barolo S (2012) Shadow enhancers: frequently asked questions about distributed cis‐regulatory information and enhancer redundancy. BioEssays 34: 135– 141 22083793 PMC3517143
  9. Baron M, Veres A, Wolock SL, Faust AL, Gaujoux R, Vetere A, Ryu JH, Wagner BK, Shen‐Orr SS, Klein AM et al (2016) A single‐cell transcriptomic map of the human and mouse pancreas reveals inter‐ and intra‐cell population structure. Cell Syst 3: 346– 360.e4 27667365 PMC5228327
  10. Beira JV, Paro R (2016) The legacy of Drosophila imaginal discs. Chromosoma 125: 573– 592 27153833 PMC5023726
  11. Bessa J, Gebelein B, Pichaud F, Casares F, Mann RS (2002) Combinatorial control of Drosophila eye development by eyeless, homothorax, and teashirt. Genes Dev 16: 2415– 2427 12231630 PMC187435
  12. Blanco J, Pauli T, Seimiya M, Udolph G, Gehring WJ (2010) Genetic interactions of eyes absent, twin of eyeless and orthodenticle regulate sine oculis expression during ocellar development in Drosophila. Dev Biol 344: 1088– 1099 20580700
  13. Bozek M, Cortini R, Storti AE, Unnerstall U, Gaul U, Gompel N (2019) ATAC‐seq reveals regional differences in enhancer accessibility during the establishment of spatial coordinates in the Drosophila blastoderm. Genome Res 29: 771– 783 30962180 PMC6499308
  14. Bravo González‐Blas C, Minnoye L, Papasokrati D, Aibar S, Hulselmans G, Christiaens V, Davie K, Wouters J, Aerts S (2019) cisTopic: cis‐regulatory topic modeling on single‐cell ATAC‐seq data. Nat Methods 16: 397– 400 30962623 PMC6517279
  15. Buenrostro JD, Giresi PG, Zaba LC, Chang HY, Greenleaf WJ (2013) Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA‐binding proteins and nucleosome position. Nat Methods 10: 1213– 1218 24097267 PMC3959825
  16. Buenrostro JD, Wu B, Litzenburger UM, Ruff D, Gonzales ML, Snyder MP, Chang HY, Greenleaf WJ (2015) Single‐cell chromatin accessibility reveals principles of regulatory variation. Nature 523: 486– 490 26083756 PMC4685948
  17. Burgess DJ (2019) Spatial transcriptomics coming of age. Nat Rev Genet 20: 317– 317 30980030
  18. Cannavò E, Khoueiry P, Garfield DA, Geeleher P, Zichner T, Gustafson EH, Ciglar L, Korbel JO, Furlong EEM (2016) Shadow enhancers are pervasive features of developmental regulatory networks. Curr Biol 26: 38– 51 26687625 PMC4712172
  19. Charlton‐Perkins M, Whitaker SL, Fei Y, Xie B, Li‐Kroeger D, Gebelein B, Cook T (2011) Prospero and Pax2 combinatorially control neural cell fate decisions by modulating Ras‐ and Notch‐dependent signaling. Neural Dev 6: 20 21539742 PMC3123624
  20. Chen H, Lareau C, Andreani T, Vinyard ME, Garcia SP, Clement K, Andrade‐Navarro MA, Buenrostro JD, Pinello L (2019a) Assessment of computational methods for the analysis of single‐cell ATAC‐seq data. Genome Biol 20: 241 31739806 PMC6859644
  21. Corces MR, Trevino AE, Hamilton EG, Greenside PG, Sinnott‐Armstrong NA, Vesuna S, Satpathy AT, Rubin AJ, Montine KS, Wu B et al (2017) An improved ATAC‐seq protocol reduces background and enables interrogation of frozen tissues. Nat Methods 14: 959– 962 28846090 PMC5623106
  22. Cusanovich DA, Reddington JP, Garfield DA, Daza RM, Aghamirzaie D, Marco‐Ferreres R, Pliner HA, Christiansen L, Qiu X, Steemers FJ et al (2018) The cis‐regulatory dynamics of embryonic development at single‐cell resolution. Nature 555: 538– 542 29539636 PMC5866720
  23. Daga A, Karlovich CA, Dumstrei K, Banerjee U (1996) Patterning of cells in the Drosophila eye by Lozenge, which shares homologous domains with AML1. Genes Dev 10: 1194– 1205 8675007
  24. Davie K, Jacobs J, Atkins M, Potier D, Christiaens V, Halder G, Aerts S (2015) Discovery of transcription factors and regulatory regions driving in vivo tumor development by ATAC‐seq and FAIRE‐seq open chromatin profiling. PLoS Genet 11: e1004994 25679813 PMC4334524
  25. Davie K, Janssens J, Koldere D, Waegeneer MD, Pech U, Kreft Ł, Aibar S, Makhzami S, Christiaens V, González‐Blas CB et al (2018) A single‐cell transcriptome atlas of the aging Drosophila brain. Cell 174: 982– 998.e20 29909982 PMC6086935
  26. Davis CA, Hitz BC, Sloan CA, Chan ET, Davidson JM, Gabdank I, Hilton JA, Jain K, Baymuradov UK, Narayanan AK et al (2018) The encyclopedia of DNA elements (ENCODE): data portal update. Nucleic Acids Res 46: D794– D801 29126249 PMC5753278
  27. Domingos PM, Brown S, Barrio R, Ratnakumar K, Frankfort BJ, Mardon G, Steller H, Mollereau B (2004) Regulation of R7 and R8 differentiation by the spalt genes. Dev Biol 273: 121– 133 15302602
  28. Dong PDS, Dicks JS, Panganiban G (2002) Distal‐less and homothorax regulate multiple targets to pattern the Drosophila antenna. Development 129: 1967– 1974 11934862
  29. Dyer MA, Livesey FJ, Cepko CL, Oliver G (2003) Prox1 function controls progenitor cell proliferation and horizontal cell genesis in the mammalian retina. Nat Genet 34: 53– 58 12692551
  30. Eberl DF, Boekhoff‐Falk G (2007) Development of Johnston's organ in Drosophila. Int J Dev Biol 51: 679– 687 17891726 PMC3417114
  31. Eden E, Navon R, Steinfeld I, Lipson D, Yakhini Z (2009) GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics 10: 48 19192299 PMC2644678
  32. Edqvist PHD, Myers SM, Hallböök F (2006) Early identification of retinal subtypes in the developing, pre‐laminated chick retina using the transcription factors Prox1, Lim1, Ap2alpha, Pax 6, Isl1, Isl2, Lim3 and Chx10. Eur J Histochem 50: 147– 154 16864127
  33. Emerald BS, Curtiss J, Mlodzik M, Cohen SM (2003) Distal antenna and distal antenna related encode nuclear proteins containing pipsqueak motifs involved in antenna development in Drosophila. Development 130: 1171– 1180 12571108
  34. Emmons RB, Duncan D, Duncan I (2007) Regulation of the Drosophila distal antennal determinant spineless. Dev Biol 302: 412– 426 17084833 PMC1876787
  35. Eng C‐HL, Lawson M, Zhu Q, Dries R, Koulena N, Takei Y, Yun J, Cronin C, Karp C, Yuan G‐C et al (2019) Transcriptome‐scale super‐resolved imaging in tissues by RNA seqFISH. Nature 568: 235– 239 30911168 PMC6544023
  36. Fang R, Preissl S, Hou X, Lucero J, Wang X, Motamedi A, Shiau AK, Mukamel EA, Zhang Y, Behrens MM et al (2019) Fast and accurate clustering of single cell epigenomes reveals cis‐regulatory elements in rare cell types. bioRxiv: 615179 10.1101/615179 [PREPRINT] · DOI
  37. Fiers MWEJ, Minnoye L, Aibar S, Bravo González‐Blas C, Kalender Atak Z, Aerts S (2018) Mapping gene regulatory networks from single‐cell omics data. Brief Funct Genomics 17: 246– 254 29342231 PMC6063279
  38. Fitzgerald DP, Bender W (2001) Polycomb group repression reduces DNA accessibility. Mol Cell Biol 21: 6585– 6597 11533246 PMC99804
  39. Forbes‐Osborne MA, Wilson SG, Morris AC (2013) Insulinoma‐associated 1a (Insm1a) is required for photoreceptor differentiation in the zebrafish retina. Dev Biol 380: 157– 171 23747542 PMC3703496
  40. Frankel N, Davis GK, Vargas D, Wang S, Payre F, Stern DL (2010) Phenotypic robustness conferred by apparently redundant transcriptional enhancers. Nature 466: 490– 493 20512118 PMC2909378
  41. Frankfort BJ, Nolo R, Zhang Z, Bellen H, Mardon G (2001) Senseless repression of rough is required for r8 photoreceptor differentiation in the developing Drosophila eye. Neuron 32: 403– 414 11709152 PMC3122332
  42. Frith MC, Li MC, Weng Z (2003) Cluster‐Buster: finding dense clusters of motifs in DNA sequences. Nucleic Acids Res 31: 3666– 3668 12824389 PMC168947
  43. Fritsch C, Bernardo‐Garcia FJ, Humberg T‐H, Mishra AK, Miellet S, Almeida S, Frochaux MV, Deplancke B, Huber A, Sprecher SG (2019) Multilevel regulation of the glass locus during Drosophila eye development. PLoS Genet 15: e1008269 31299050 PMC6655844
  44. Froldi F, Szuperak M, Weng C‐F, Shi W, Papenfuss AT, Cheng LY (2015) The transcription factor Nerfin‐1 prevents reversion of neurons into neural stem cells. Genes Dev 29: 129– 143 25593306 PMC4298133
  45. Furlong EEM, Andersen EC, Null B, White KP, Scott MP (2001) Patterns of gene expression during Drosophila mesoderm development. Science 293: 1629– 1633 11486054
  46. Fuxman Bass JI, Reece‐Hoyes JS, Walhout AJM (2016) Gene‐centered yeast one‐hybrid assays. Cold Spring Harb Protoc 2016: 1039– 1043 PMC5443116 27934693
  47. Gary S, Levin M (1996) Transcriptional repression in development. Curr Opin Cell Biol 8: 358– 364 8743887
  48. Gramates LS, Marygold SJ, dos Santos G, Urbano J‐M, Antonazzo G, Matthews BB, Rey AJ, Tabone CJ, Crosby MA, Emmert DB et al (2017) FlyBase at 25: looking to the future. Nucleic Acids Res 45: D663– D671 27799470 PMC5210523
  49. Granja JM, Klemm S, McGinnis LM, Kathiria AS, Mezger A, Corces MR, Parks B, Gars E, Liedtke M, Zheng GXY et al (2019) Single‐cell multiomic analysis identifies regulatory programs in mixed‐phenotype acute leukemia. Nat Biotechnol 37: 1458– 1465 31792411 PMC7258684
  50. Hamm DC, Larson ED, Nevil M, Marshall KE, Bondra ER, Harrison MM (2017) A conserved maternal‐specific repressive domain in Zelda revealed by Cas9‐mediated mutagenesis in Drosophila melanogaster. PLoS Genet 13: e1007120 29261646 PMC5752043
  51. Herrmann C, Van de Sande B, Potier D, Aerts S (2012) i‐cisTarget: an integrative genomics method for the prediction of regulatory features and cis‐regulatory modules. Nucleic Acids Res 40: e114 22718975 PMC3424583
  52. Higashijima S, Kojima T, Michiue T, Ishimaru S, Emori Y, Saigo K (1992) Dual Bar homeo box genes of Drosophila required in two photoreceptor cells, R1 and R6, and primary pigment cells for normal eye development. Genes Dev 6: 50– 60 1346120
  53. Iyer J, Wang Q, Le T, Pizzo L, Grönke S, Ambegaokar SS, Imai Y, Srivastava A, Troisí BL, Mardon G et al (2016) Quantitative assessment of eye phenotypes for functional genetic studies using Drosophila melanogaster. G3 (Bethesda) 6: 1427– 1437 26994292 PMC4856093
  54. Jiang L, Chen H, Pinello L, Yuan G‐C (2016) GiniClust: detecting rare cell types from single‐cell gene expression data with Gini index. Genome Biol 17: 144 27368803 PMC4930624
  55. Jory A, Estella C, Giorgianni MW, Slattery M, Laverty TR, Rubin GM, Mann RS (2012) A survey of 6,300 genomic fragments for cis‐regulatory activity in the imaginal discs of Drosophila melanogaster. Cell Rep 2: 1014– 1024 23063361 PMC3483442
  56. Jusiak B, Wang F, Karandikar UC, Kwak S‐J, Wang H, Chen R, Mardon G (2014) Genome‐wide DNA binding pattern of the homeodomain transcription factor Sine oculis (So) in the developing eye of Drosophila melanogaster. Genomics Data 2: 153– 155 25126519 PMC4128500
  57. Karaiskos N, Wahle P, Alles J, Boltengagen A, Ayoub S, Kipar C, Kocks C, Rajewsky N, Zinzen RP (2017) The Drosophila embryo at single‐cell transcriptome resolution. Science 358: 194– 199 28860209
  58. Karim MR, Moore AW (2011) Convergent local identity and topographic projection of sensory neurons. J Neurosci 31: 17017– 17027 22114271 PMC6623857
  59. Korsunsky I, Millard N, Fan J, Slowikowski K, Zhang F, Wei K, Baglaenko Y, Brenner M, Loh P, Raychaudhuri S (2019) Fast, sensitive and accurate integration of single‐cell data with harmony. Nat Methods 16: 1289– 1296 31740819 PMC6884693
  60. Kuzin A, Brody T, Moore AW, Odenwald WF (2005) Nerfin‐1 is required for early axon guidance decisions in the developing Drosophila CNS. Dev Biol 277: 347– 365 15617679
  61. de Laat W, Duboule D (2013) Topology of mammalian developmental enhancers and their regulatory landscapes. Nature 502: 499– 506 24153303
  62. Lam DD, de Souza FSJ, Nasif S, Yamashita M, López‐Leal R, Otero‐Corchon V, Meece K, Sampath H, Mercer AJ, Wardlaw SL et al (2015) Partially redundant enhancers cooperatively maintain mammalian pomc expression above a critical functional threshold. PLoS Genet 11: e1004935 25671638 PMC4335486
  63. Li LM, Arnosti DN (2011) Long‐ and short‐range transcriptional repressors induce distinct chromatin states on repressed genes. Curr Biol 21: 406– 412 21353562 PMC3061390
  64. Liu L, Liu C, Quintero A, Wu L, Yuan Y, Wang M, Cheng M, Leng L, Xu L, Dong G et al (2019) Deconvolution of single‐cell multi‐omics layers reveals regulatory heterogeneity. Nat Commun 10: 1– 10 30692544 PMC6349937
  65. Lopes CS, Casares F (2015) Eye selector logic for a coordinated cell cycle exit. PLoS Genet 11: e1004981 25695251 PMC4335009
  66. Minakhina S, Tan W, Steward R (2011) JAK/STAT and the GATA factor Pannier control hemocyte maturation and differentiation in Drosophila. Dev Biol 352: 308– 316 21295568 PMC3065540
  67. Mlodzik M, Hiromi Y, Weber U, Goodman CS, Rubin GM (1990) The Drosophila seven‐up gene, a member of the steroid receptor gene superfamily, controls photoreceptor cell fates. Cell 60: 211– 224 2105166
  68. Nagano T, Lubling Y, Yaffe E, Wingett SW, Dean W, Tanay A, Fraser P (2015) Single‐cell Hi‐C for genome‐wide detection of chromatin interactions that occur simultaneously in a single cell. Nat Protoc 10: 1986– 2003 26540590
  69. Nelson BR, Hartman BH, Georgi SA, Lan MS, Reh TA (2007) Transient inactivation of Notch signaling synchronizes differentiation of neural progenitor cells. Dev Biol 304: 479– 498 17280659 PMC1979095
  70. Nitzan M, Karaiskos N, Friedman N, Rajewsky N (2019) Gene expression cartography. Nature 576: 132– 137 31748748
  71. Nolo R, Abbott LA, Bellen HJ (2000) Senseless, a Zn finger transcription factor, is necessary and sufficient for sensory organ development in Drosophila. Cell 102: 349– 362 10975525
  72. Osterwalder M, Barozzi I, Tissières V, Fukuda‐Yuzawa Y, Mannion BJ, Afzal SY, Lee EA, Zhu Y, Plajzer‐Frick I, Pickle CS et al (2018) Enhancer redundancy provides phenotypic robustness in mammalian development. Nature 554: 239– 243 29420474 PMC5808607
  73. Ostrin EJ, Li Y, Hoffman K, Liu J, Wang K, Zhang L, Mardon G, Chen R (2006) Genome‐wide identification of direct targets of the Drosophila retinal determination protein eyeless. Genome Res 16: 466– 476 16533912 PMC1457028
  74. Oyallon J, Apitz H, Miguel‐Aliaga I, Timofeev K, Ferreira L, Salecker I (2012) Regulation of locomotion and motoneuron trajectory selection and targeting by the Drosophila homolog of Olig family transcription factors. Dev Biol 369: 261– 276 22796650 PMC3464432
  75. Pappu KS, Ostrin EJ, Middlebrooks BW, Sili BT, Chen R, Atkins MR, Gibbs R, Mardon G (2005) Dual regulation and redundant function of two eye‐specific enhancers of the Drosophila retinal determination gene dachshund. Development 132: 2895– 2905 15930118
  76. Pataskar A, Jung J, Smialowski P, Noack F, Calegari F, Straub T, Tiwari VK (2016) NeuroD1 reprograms chromatin and transcription factor landscapes to induce the neuronal program. EMBO J 35: 24– 45 26516211 PMC4718003
  77. Pepple KL, Atkins M, Venken K, Wellnitz K, Harding M, Frankfort B, Mardon G (2008) Two‐step selection of a single R8 photoreceptor: a bistable loop between senseless and rough locks in R8 fate. Development 135: 4071– 4079 19004852 PMC3135101
  78. Perry MW, Boettiger AN, Bothma JP, Levine M (2010) Shadow enhancers foster robustness of Drosophila gastrulation. Curr Biol 20: 1562– 1567 20797865 PMC4257487
  79. Pervolarakis N, Nguyen Q, Gutierrez G, Sun P, Jhutty D, Zheng GX, Nemec CM, Dai X, Watanabe K, Kessenbrock K (2019) Integrated single‐cell transcriptomics and chromatin accessibility analysis reveals novel regulators of mammary epithelial cell identity. bioRxiv: 740746 10.1101/740746 [PREPRINT] PMC7874899 33086071 · DOI
  80. Pliner HA, Packer JS, McFaline‐Figueroa JL, Cusanovich DA, Daza RM, Aghamirzaie D, Srivatsan S, Qiu X, Jackson D, Minkina A et al (2018) Cicero predicts cis‐regulatory DNA interactions from single‐cell chromatin accessibility data. Mol Cell 71: 858– 871.e8 30078726 PMC6582963
  81. Potier D, Davie K, Hulselmans G, Naval Sanchez M, Haagen L, Huynh‐Thu VA, Koldere D, Celik A, Geurts P, Christiaens V et al (2014) Mapping gene regulatory networks in Drosophila eye development by large‐scale transcriptome perturbations and motif inference. Cell Rep 9: 2290– 2303 25533349
  82. Rivera J, Keränen SVE, Gallo SM, Halfon MS (2019) REDfly: the transcriptional regulatory element database for Drosophila. Nucleic Acids Res 47: D828– D834 30329093 PMC6323911
  83. Rodriques SG, Stickels RR, Goeva A, Martin CA, Murray E, Vanderburg CR, Welch J, Chen LM, Chen F, Macosko EZ (2019) Slide‐seq: a scalable technology for measuring genome‐wide expression at high spatial resolution. Science 363: 1463– 1467 30923225 PMC6927209
  84. Roignant J‐Y, Treisman JE (2009) Pattern formation in the Drosophila eye disc. Int J Dev Biol 53: 795– 804 19557685 PMC2713679
  85. Schindelin J, Arganda‐Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B et al (2012) Fiji: an open‐source platform for biological‐image analysis. Nat Methods 9: 676– 682 22743772 PMC3855844
  86. Sen S, Hartmann B, Reichert H, Rodrigues V (2010) Expression and function of the empty spiracles gene in olfactory sense organ development of Drosophila melanogaster. Development 137: 3687– 3695 20940227
  87. Shlyueva D, Stampfel G, Stark A (2014) Transcriptional enhancers: from properties to genome‐wide predictions. Nat Rev Genet 15: 272– 286 24614317
  88. Small S, Blair A, Levine M (1992) Regulation of even‐skipped stripe 2 in the Drosophila embryo. EMBO J 11: 4047– 4057 1327756 PMC556915
  89. Southall TD, Davidson CM, Miller C, Carr A, Brand AH (2014) Dedifferentiation of neurons precedes tumor formation in lola mutants. Dev Cell 28: 685– 696 24631403 PMC3978655
  90. Stuart T, Butler A, Hoffman P, Hafemeister C, Papalexi E, Mauck WM, Hao Y, Stoeckius M, Smibert P, Satija R (2019) Comprehensive integration of single‐cell data. Cell 177: 1888– 1902.e21 31178118 PMC6687398
  91. Stultz BG, Park SY, Mortin MA, Kennison JA, Hursh DA (2012) Hox proteins coordinate peripodial decapentaplegic expression to direct adult head morphogenesis in Drosophila. Dev Biol 369: 362– 376 22824425 PMC3427764
  92. Suo S, Zhu Q, Saadatpour A, Fei L, Guo G, Yuan G‐C (2018) Revealing the critical regulators of cell identity in the mouse cell atlas. Cell Rep 25: 1436– 1445.e3 30404000 PMC6281296
  93. Supek F, Bošnjak M, Škunca N, Šmuc T (2011) REVIGO summarizes and visualizes long lists of gene ontology terms. PLoS One 6: e21800 21789182 PMC3138752
  94. Thornton CA, Mulqueen RM, Torkenczy KA, Lowenstein EG, Fields AJ, Steemers FJ, Wright KM, Adey AC (2019) Spatially‐mapped single‐cell chromatin accessibility (Genetics) PMC7904839 33627658
  95. Tiklová K, Tsarouhas V, Samakovlis C (2013) Control of airway tube diameter and integrity by secreted chitin‐binding proteins in Drosophila. PLoS One 8: e67415 23826295 PMC3691276
  96. Torre E, Dueck H, Shaffer S, Gospocic J, Gupte R, Bonasio R, Kim J, Murray J, Raj A (2018) Rare cell detection by single cell RNA sequencing as guided by single molecule RNA FISH. Cell Syst 6: 171– 179.e5 29454938 PMC6078200
  97. Tsuji T, Sato A, Hiratani I, Taira M, Saigo K, Kojima T (2020) Requirements of Lim1, a Drosophila LIM‐homeobox gene, for normal leg and antennal development. Development 127: 4315– 4323 11003832
  98. Warde‐Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, Franz M, Grouios C, Kazi F, Lopes CT et al (2010) The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res 38: W214– W220 20576703 PMC2896186
  99. Welch JD, Kozareva V, Ferreira A, Vanderburg C, Martin C, Macosko EZ (2019) Single‐cell multi‐omic integration compares and contrasts features of brain cell identity. Cell 177: 1873– 1887.e17 31178122 PMC6716797
  100. Xi H, Shulha HP, Lin JM, Vales TR, Fu Y, Bodine DM, McKay RDG, Chenoweth JG, Tesar PJ, Furey TS et al (2007) Identification and characterization of cell type‐specific and ubiquitous chromatin regulatory structures in the human genome. PLoS Genet 3: e136 17708682 PMC1950163
  101. Yuasa Y, Okabe M, Yoshikawa S, Tabuchi K, Xiong W‐C, Hiromi Y, Okano H (2003) Drosophila homeodomain protein REPO controls glial differentiation by cooperating with ETS and BTB transcription factors. Development 130: 2419– 2428 12702656

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Authors
Bravo González‐Blas, C., Quan, X., Duran‐Romaña, R., Taskiran, I. I., Koldere, D., Davie, K., Christiaens, V., Makhzami, S., Hulselmans, G., de Waegeneer, M., Mauduit, D., Poovathingal, S., Aibar, S., & Aerts, S.
Affiliations
VIB-KU Leuven Center for Brain & Disease Research (BE)
Corresponding author
Aerts, Stein
ORCID
Venue
Molecular Systems Biology
Publisher
Springer Science and Business Media LLC
Published
2020-05-01
Volume
16
Issue
5
Pages
e9438-e9438
ISSN
1744-4292 (ISSN-L)
DOI
10.15252/msb.20209438
PMC
PMC7237818
OpenAlex
W3026792884
Cited by
88
References
16
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4.95
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journal article
Language
en
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Locations
  • Molecular Systems Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Lirias (KU Leuven) (submittedVersion, other-oa)
  • Lirias (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • European Research Council (724226_cis‐CONTROL)
  • KU Leuven (PF/10/016)
  • Fonds Wetenschappelijk Onderzoek (11F1519N, G.0791.14, G.0C04.17)
  • Herculesstichting (AKUL/13/41)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
Keywords
enhancer identification, chromatin accessibility, single-cell transcriptomics, single-cell ATAC-seq, spatial integration, gene regulatory networks, cell type-specific enhancers, Prospero, neuronal differentiation, enhancer activity
MeSH terms
Chromatin Immunoprecipitation Sequencing, Animals, Cell Differentiation, Chromatin, Drosophila, Enhancer Elements, Genetic, Eye, Gene Expression Regulation, Immunohistochemistry, Larva, Nerve Tissue Proteins, Nuclear Proteins, Photoreceptor Cells, Promoter Regions, Genetic, Transcription Factors, Gene Expression Profiling, Genomics, Drosophila Proteins, Databases, Genetic, Animals, Genetically Modified, Quantitative Trait Loci, Gene Regulatory Networks, Arthropod Antennae, Epigenomics, Single-Cell Analysis, Transcriptome, Spatio-Temporal Analysis, Gene Ontology

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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